Alcohol and tobacco use and addiction are leading causes of morbidity and mortality in the USA and worldwide. These behaviors do not occur in isolation. Individuals who drink alcohol excessively are much more likely to smoke, and those who smoke are more likely to drink, with family studies consistently finding that genetic predispositions contribute to these relationships. Inherited genetic variation plays a substantial role in these behaviors with genome-wide association meta-analyses detecting >10 loci associated with heaviness of smoking, smoking initiation and cessation, alcohol use, or alcohol dependence. Such studies have discovered small individual effects of common genetic variants on these complex behaviors, with no variants clearly affecting both smoking and drinking. Much larger samples are now available to discover additional common and rare loci associated with smoking and drinking behavior to provide insight into the biological bases of these behaviors. To do this, we have formed a consortium of many large participating studies with existing study samples. We will finely map the genome with improved imputation, rare variant genotyping arrays, and whole genome sequencing to provide the genomic resolution necessary to identify rare and common variants that contribute to smoking and alcohol use, as well as disentangle competing genetic mechanisms. We will develop novel methods to test for shared genetic etiology, or pleiotropy, to directly test whether any particular locus influences both smoking and drinking, and contributes to the correlation between these behaviors. Finally, we will functionally annotate these dense genomic maps to characterize the nature of discovered loci. The results of this project will stimulate a wide range of follow-up experiments to characterize discovered loci.